1. Field of the Invention
This invention relates to a rubber composition for a medical treatment or a medicament, and a crosslinked product thereof, more specifically, a rubber composition used for an instrument for a medical treatment or medicament, or for a rubber stopper for a medicament or a rubber article for a medical treatment, in particular, comprising, as a predominant component, isobutylene copolymers capable of being readily subjected to a radiation treatment.
2. Description of the Prior Art
Use of rubbers in the fields of instruments or containers for medical treatments and medicaments has been started as natural rubbers from the olden time and gradually, synthetic rubbers have often been used. At the present time, thermoplastic elastomers or mixtures with synthetic resins have widely been used. As a test method of such a rubber composition article of this kind (which will hereinafter be referred to as xe2x80x9crubber articlexe2x80x9d), there are xe2x80x9c48 Test Method of Rubber Stopper for Fluid Administrationxe2x80x9d and xe2x80x9c49 Test Method of Plastic Container for Fluid Administrationxe2x80x9d according to Japanese Pharmacopoeia of 13th Revision, which will hereinafter be referred to as JP 13, in which the passing values are provided. Furthermore, in the field of rapidly advancing articles for medical treatments and for medicaments, it is the present situation that high quality materials and products have been required.
Since about 1950, isobutylene-isoprene copolymer rubbers (which will hereinafter be referred to as xe2x80x9cIIRxe2x80x9d sometimes), etc. have been recommended as a material suitable for sanitary rubber articles, but cross-linking of IIR is so difficult that a combination of a strong cross-linking agent and cross-linking aid is required. Such a combination is for example described in R. T. Vanderbilt, xe2x80x9cRUBBER HANDBOOKxe2x80x9d, xe2x80x9cVanderbiltxe2x80x9d (published 1968), xe2x80x9cGosei Gomu Kako Gijutsu Zensho (Synthetic Rubber Working Technique Complete Book)xe2x80x9d, Vol. 8, xe2x80x9cButyl Rubberxe2x80x9d, Taiseisha, (published 1973), etc.
As to the cross-linking technique, there have been proposed a process for the production of adhesives by vulcanization of IIR at a low temperature (JP-A-60-130665), a method for cross-linking IIR in the coexistence of three materials of quinoid, organo peroxides and acryloyl monomer (JP-A-62-074934), cross-linking of IIR in the presence of organo peroxides and polyfunctional monomers having electron-withdrawing groups (JP-A-6-172547), etc.
As a rubber article in the field of requiring high sanitary property are known a rubber article comprising IIR compounded with a fine powder of ultrahigh molecular weight polyethylene (JP-A-60-144346), cross-linking of IIR by joint use of special organo peroxides and maleimides (JP-A-4-213347), etc.
On the other hand, it is apparent that use of butyl rubber most excellent in cleanness as well as gaseous permeability resistance is most suitable as a material of a rubber stopper for medicaments, needing a high sealing degree, for the rubber formulation.
As a method for the sterilization of containers for injections (according to Japanese Pharmacopoeia, a rubber stopper is also defined as a container) and for the sterilization of instruments for medical treatments, the ISO Guide Line or Japanese Pharmacopoeia describes that among a high pressure steam sterilization, gaseous sterilization with ethylene oxide and radiation sterilization, a high pressure steam sterilization is exclusively used for rubber stoppers for medicaments and gaseous sterilization and radiation sterilization are carried out for plastic instruments for medical treatments.
However, the gaseous sterilization method has been considered as a question as to the safety of residual gases in containers or instruments by FDA, etc. and in addition, items for controlling the sterilization step are considered difficult, because of difficulty in controlling or validating a gas concentration or gas temperature distribution, thus making hard identification of the sterilization integrity. Sterilization of a glass container for an injection, rubber stopper thereof or heat resistance plastic instrument for a medical treatment has ordinarily been carried out by a high pressure steam sterilization (autoclave sterilization) from the olden time, which has met a problem with respect to uniform controlling of the temperature in the autoclave and thus, has been subjected to improvement of the system.
For the production of a sterilized container for an injection agent or sterilized instrument for a medical treatment, a sterile test of a final product is an obligation and without passing this test, shipping of the product is impossible, which constitutes a large neck for improvement of the productivity in a production process for instruments for medical treatments. The sterile test requires two weeks until the test results are attained, during which a further step of charging a medicament as a subsequent process cannot be carried out, for example, in the case of a container for the sterile formulation.
FDA in USA has lately proposed the conception that it is equal to adaptability results in the sterile test to control the Parametric Release (shipping being dependent on the parameter administration), that is, the important Parameter for determining the precision of the process and to confirm and record the administrated state. Accordingly, as a first example, there is a sterilization operation utilizing a radiation and in the case of a product sterilized by this method, use and shipping of the product can be allowed by measurement and recording of the absorbed doses of materials sterilized such as containers for injections or instruments for medical treatments before the results of the sterile test. This conception is generally referred to as xe2x80x9cDosimetric Releasexe2x80x9d (shipping is allowed by dose measurement).
Various synthetic rubbers as raw materials are largely different in radiation resistance depending on their chemical structures, presence or absence of double bond or vinylidene type structure, cross-linking methods, presence or absence of quaternary carbon. EPM and EPDM (ethylene-propylene rubbers and ethylene-propylene terpolymer) having no double bond in the main chain have some problem on the vulcanization property as to working of the rubber, but are used as a material for rubber articles for medical treatments as disclosed by the present inventors in JP-A-62-176455.
On the other hand, the chemical structure of butyl rubber most suitable as a material of a rubber stopper for a medicament consists in having quaternary carbon in the main chain, isobutylene part, so that when applying a high energy such as radiation to the rubber molecule, polymer radicals are produced and the isobutylene part is cut off, resulting in oxidation deterioration. This chemical phenomenon is harder to occur in the case of chemically modified butyl rubber, such as by chlorine or bromine, but the tendency is not changed that it is inferior to any synthetic rubbers in radiation resistance.
The sterilization assurance level (SAL) of a rubber stopper for a medicament or an instrument for a medical treatment is ordinarily provided at 10xe2x88x926 and the radiation dose is often used at 25 kGy.
As a radiation, there are xcex1-rays (atomic nucleus of helium), xcex2-rays (electron beam) and xcex3-rays, and for the sterilization, there are used xcex2-rays prepared by an accelerator and xcex3-rays generated from 60Co or 137Cs. The electron beam has such a higher dose (several 104 times of xcex3-rays) that the sterilization operation time is short, but only gives a small transmission because of being a particle beam. On the other hand, the xcex3-rays (X-rays being the same) is a kind of electromagnetic waves and exhibits a large transmission capacity, but takes a longer operation time because of having a smaller dose than the electron beam.
In the case of sterilizing a rubber article by the large transmission xcex3-rays, the radiation sterilization can be effected even if it is in the form of an article with a large apparent volume wrapped by a corrugated cardboard, but the xcex3-rays having a smaller dose takes a longer operation time extending to several hours for irradiating a predetermined dose. Such a long irradiation time means a long total irradiation time for an article to be irradiated (article to be sterilized), i.e. a rubber stopper for a medicament, thus resulting in exposure of polymer radicals or peroxyradicals in the rubber, that is, rubber itself to irradiation for a long time leading to oxidation deterioration thereof.
In the rubber technique, it is an antinomic proposition to increase a irradiation dose so as to raise the sterilization assurance level and to suppress deterioration of the rubber material, which is an important problem to be solved in carrying out the radiation sterilization.
It is an object of the present invention to provide a rubber composition or its crosslinked product used for a rubber stopper for a medicament or a rubber article for a medical treatment, suitable for radiation treatments, whereby the above described problems can be resolved.
It is another object of the present invention to provide a method for the treatment comprising applying a radiation to a rubber composition comprising an isobutylene copolymer, as a predominant component, with a density of at most 0.95 and thereby carrying out crosslinking of said composition or sterilization of the crosslinked product thereof.
These objects can be attained by the following inventions:
(1) a rubber composition or its crosslinked product used for a rubber stopper for a medicament or a rubber article for a medical treatment, comprising an isobutylene copolymer, as a predominant component, with a density of at most 0.95, capable of being readily subjected to a radiation treatment,
(2) the rubber composition or its crosslinked product, as described in the foregoing (1), wherein the isobutylene copolymer, as a predominant component, is at least one member selected from the group consisting of isobutylene-isoprene copolymers (IIR), chlorinated isobutylene-isoprene copolymers (C-IIR), brominated isobutylene-isoprene copolymers (B-IIR), crosslinked isobutylene-isoprene-divinylbenzene ternary copolymers (XL-IIR) and brominated isobutylene-paramethylstyrene copolymers (BIMS) and
(3) a method for the treatment comprising applying a radiation to a rubber composition comprising an isobutylene copolymer, as a predominant component, with a density of at most 0.95 and thereby carrying out crosslinking of said composition or sterilization of the crosslinked product thereof.
In the above described invention (1), the isobutylene copolymer means a copolymer comprising 95 to 99.5 weight % of isobutylene group and 0.5 to 5 weight % of isoprene group, which is ordinarily called IIR. U.S. Pat. Nos. 2,356,128 and 3,816,371 have proposed IIR whose isoprene group content is increased to 30 weight % and such copolymers have commercially been available for some period but have lately disappeared from the market since the prices and uses of the copolymers have not been accepted thereby.
Thus, the object of the present invention is concerned with a generally marketed one as IIR. IIR is an excellent rubber having the feature largely dependent on its isobutylene group and consisting in the chemical stability such as represented by an unsaturated degree of 0, very low gas permeability, high resistance to strong acids such as concentrated sulfuric acid, concentrated hydrochloric acid, etc., to strong alkalies such as concentrated NaOH, etc., to peroxides such as H2O2, etc., and having a heat resistance as well as a strong stickiness.
In the isobutylene copolymer of the present invention, the isobutylene group is represented by a recurring unit shown by the following formula (1): 
In this general formula, n is a number of 500 to 150,000.
Since crosslinking of IIR is very difficult, it is known so as to be readily crosslinked to convert it into chlorinated isobutylene-isoprene copolymers (C-IIR) or brominated isobutylene-isoprene copolymers (B-IIR), brominated isobutylene-paramethylstyrene coploymers (BINS) by dissolving IIR in a solvent and then passing through it chlorine gas or bromine gas, and isobutylene-isoprene-divinylbenzene ternary coploymers (XL-IIR) by partially crosslinking IIR with divinylbenzene.
Accordingly, the isobutylene-isoprene copolymerized rubbers of the present invention are exemplified by IIR, BIIR, CIIR and XL-IIR, as described above, which will hereinafter generally be referred to as xe2x80x9cIIR memberxe2x80x9d.
As the isobutylene copolymers, there can be used isobutylene-isoprene copolymers (IIR), their chlorinated ones (C-IIR) or brominated ones (B-IIR) or brominated isobutylene-paramethylstyrene coploymers (BIMS), but above all, it is most preferable to use isobutylene-isoprene-divinylbenzene ternary coploymers (XL-IIR) excellent in radiation resistance.
In the present invention, the above described isobutylene copolymers are used as a predominant component, but ordinarily, there can be added thereto thermoplastic resins (plastics or thermoplastic rubbers, TPR) such as high density polyethylene ultrahigh molecular weight polyethylene, methylpentene polymers (TPX), polybutene-1, styrene-ethylene-butylene-styrene block copolymers (SEBS), ethylene-propylene copolymers (EPM), cyclic olefin homopolymers (COP), cyclic olefin-ethylene copolymers (COC), etc. in a proportion of 10 to 50 weight %.
In the present invention, it is a particularly preferred embodiment that the above described isobutylene copolymers is in a proportion of 70 to 80 weight % to the rubber composition for a medical treatment or medicament.
Furthermore, it is another particularly preferred embodiment that an inorganic reinforcing agent and/or filler in a proportion of 3 to 7 weight parts to 100 weight parts of the above described butyl rubber or isobutylene copolymers and no heavy metal compound is added.
The present invention further provides a rubber article for a medical treatment or a medicament comprising the above described rubber composition crosslinked. This crosslinking is preferably carried out at least one time statically or dynamically using at least one crosslinking means selected from natural crosslinking, heating, using light and irradiating.
The above described crosslinking is generally carried out using a suitable crosslinking agent. As the crosslinking agent, there are ordinarily used, for example, 1,1-di(t-butylperoxy)-3,3,5-trimethylcyclohexane, t-butylcumylperoxide, di-cumylperoxide, 2,5-dimethyl-2,5-di(t-butylperoxy)hexane or -hexin-3, t-butyl-peroxyisopropylcarbonate, benzoylperoxide, di-t-butylperoxide, 2,2xe2x80x2-di-t-butyl-peroxybutane, di-isobutylperoxide, 3-benzoylperoxy-3-methylbutyltriethysilane, pertrimellitic acid tri-t-butyl ester, 3,3xe2x80x2,4,4xe2x80x2-tetra(t-butylperoxycarbonyl)-benzophenone, di-t-butylperoxide, t-butylperoxybenzoate, 2,5-di(t-butylperoxy)-2,5-dimethylhexane and the like.
In the rubber composition of the present invention, the isobutylene copolymer is in a proportion of 70 to 80 weight %, since if less than 70 weight %, the features of the copolymers, that is, the gas non-permeability, heat resistance, highly viscous property and chemical stability of polyisobutylene are decreased, while if more than 80 weight %, the deformation and compressive strain of the product are increased. Thus, the product is not preferred as a material for a medical treatment or medicament.
The proportion of the crosslinking compound in the rubber composition according to the present invention is 0.5 to 5 weight parts to 100 weight parts of the IIR member or isobutylene copolymers, since if less than 0.5 weight part, the quantity of strains such as compressive strain is increased to be unsuitable for the use of the present invention, while if more than 5 weight parts, the amounts of expensive additives are increased and not suitable in economy.
To the rubber composition of the present invention can be added at least one member selected from the group consisting of inorganic reinforcing agents or fillers, organic reinforcing agents or fillers, antioxidants, stabilizers and the like in a proportion of 0.5 to 50 weight parts to 100 weight parts of IIR or isobutylene copolymers.
As the inorganic reinforcing agent, for example, silica type fillers, clays, titanium oxide, etc. can be used which are capable of improving thermal and electric conductivity during crosslinking of rubbers, resulting in uniform crosslinking and prevention of the product from deformation. The amount of the inorganic reinforcing agent to be added is preferably in a proportion of 3 to 7 weight parts to 100 weight parts of IIR or isobutylene copolymers, since if more than 7 weight parts, fine grains are caused to be released from the rubber product surfaces, while if less than 3 weight parts, the above described effects cannot be given.
In the present invention, heavy metal compounds having a specific gravity of at least 6.0, such as of lead, cadmium, platinum, etc. are not compounded. It is known that lead compounds such as lead peroxide and lead oxide, etc., chloroplatinic acid, colloidal platinum, tin chlorides, etc. function as a crosslinking aid to shorten the crosslinking time or to improve the crosslinking density of IIR member or isobutylene copolymers, but in the present invention, these compounds are not used even if the crosslinking effect is present, since the presence of heavy metals should be avoided in the application field as a final rubber artice. Because of using no such compounds, the rubber composition of the present invention is capable of giving high sanitary property and passing the standards of various official propvisions.
To the rubber composition of the present invention can further be added organic type reinforcing agents, antioxidants, stabilizers, etc. As the particularly preferred organic type reinforcing agents, there are ultrahigh molecular weight polyethylene powder (e.g. Hizexmillionmeter 240, commercial name), polyethylene (PE), polypropylene (PP), polycarbonate (PC), polybutadiene (BR), 1,2-bonded styrene butadiene (SBR), polysulfone type resins (e.g. VDEL, commercial name) and the like, at least one of which can be used in a proportion of 20 to 30 weight parts to 100 weight parts of the IIR member or isobutylene copolymers.
As the crosslinking assistant, there can be used silane coupling agents such as vinyltrimethoxysilane, xcex3-methacryloxypropyltrimethoxysilane, xcex3-glycidoxypropyltrimethoxysilane, xcex3-mercaptopropyltrimethoxysilane, xcex2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, etc., tetrakis(2-ethylhexyl) titanate, dipropoxy-bis(acetylacetonato)titan [titanacetylacetonato], sulfur, stearic acid, triallyl cyanurate, triallyl isocyanurate, trimethylolpropane trimethacrylate, 1,2-polybutadiene, m-phenylenebismaleimide, magnesium oxide, titanium oxide, zinc oxide, bis(2-diethylamino)-4,6-dimercapto-s-triazine and the like, at least one of which can be added in a proportion of 0 to 5 weight parts to 100 weight parts of IIR member or isobutylene copolymers.
Furthermore, as the antioxidant, for example, there can be used 2,6-di-t-butyl-p-cresol, n-octadecyl-xcex2-(4xe2x80x2-hydroxy-3xe2x80x2,5xe2x80x2-di-t-butylphenyl)propionate, tetrakis[methylene-3(3xe2x80x2,5xe2x80x2-d-t-butyl-4-hydroxyphenyl)propionate]methane and the like, at least one of which can be added in a proportion of 0.05 to 1 weight part to 100 weight parts of IIR member or isobutylene copolymers.
The variety and quantity of compounding agents are varied with a number of factors, for example, instruments for medical treatments, kinds of instruments for medicaments, required properties, effects, machines or tools for shaping or working, producibility, unit costs, etc. Since shaping and crosslinking of the IIR member are one of the largest difficulties, it is important to prepare rubber articles having the most suitable properties for medical treatments and medicaments by combining many factors for designing products.
In the present invention, the crosslinking is carried out by either a static method comprising crosslinking and shaping using a metallic mold or a dynamic method shaping after dynamic crosslinking using an extruder, internal mixer, curl, etc.
As the crosslinking means, there can be used heating, light irradiation or application of radiation. In the case of the thermal crosslinking, there are a method comprising heating at a temperature of 140 to 200xc2x0 C. in a metallic mold and thus effecting crosslinking and shaping or a method comprising heating at a temperature of 140 to 300xc2x0 C. in an internal mixer or extruder, thus effecting dynamic crosslinking and then shaping.
The crosslinking by radiation can preferably be carried out by application of an absorbed dose of 50 kGy to 200 kGy, in particular, electron beam. In a special case, a crosslinking agent is added in a proportion of at least 0.5 weight part to 100 weight parts of a composition, as an ordinary embodiment, corresponding to a minimum quantity required for the static crosslinking or dynamic crosslinking, and the thus shaped article is taken out of a metallic mold, subjected to punching into a sheet and then to application of an electron beam with an absorbed dose of 50 kGy to 200 kGy again.
The rubber article of the present invention, obtained by crosslinking and shaping, is then rinsed and if necessary, subjected to a known treatment as an article for a medical treatment or an article for a medicament, for example, to a sterilization treatment. Practical crosslinking and aftertreatment conditions will concretely be illustrated by the following examples.
In the above described invention (3), application of a radiation to the rubber composition is carried out for the purpose of crosslinking the composition or sterilizing the crosslinked product thereof, and the radiation resistance thereof is dependent on the physical properties, chemical structures, presence or absence of double bonds or vinylidene type structures, crosslinking methods, presence or absence of quaternary carbons, of the composing resin components.
In the present invention, the radiation used includes xcex1-rays (atomic nucleus of helium), xcex2-rays (electron beam) and xcex3-rays. For the sterilization, xcex2-rays (electron beam) made by an accelerator, xcex3-rays generated from 60Co or 107Cs are preferable. Since the electron beam has a very high dose (as large as several 104 times xcex3-rays), the sterilizing treatment time can be shortened, but its transmission capacity is smaller because of being a corpuscular beam. On the other hand, the xcex3-rays (x-rays is the same) is a kind of electromagnetic waves and exhibits a large transmission capacity, but takes a longer operation time because of having a smaller dose than the electron beam.
In the case of sterilizing a rubber article by the large transmission xcex3-rays, the radiation sterilization can readily be effected even if it is in the form of an article with a large apparent volume wrapped by a corrugated cardboard, but the xcex3-rays having a smaller dose takes a longer operation time extending to several hours for irradiating a predetermined dose.
As illustrated before, when radiation is applied to sterilize a vulcanized rubber (rubber article), the exposure dose (absorption dose) is the larger, the rubber article is the more largely affected. In the case of butyl rubber (IIR member), in particular, this tendency is present, so the lower limit of the exposure dose should necessarily be provided with a higher level when an article to be sterilized has a higher degree of microorganism contamination (larger number of adhered bacteria).
In ISO 11171-1997, it is provided that when medical devices or health care products are subjected to radiation sterilization, the total number of adhered bacteria per one product must be at most 100. Assuming that Do value of Bacillus Pumilus is 1.7 kGy and all the adhered bacteria are present on the inner surface of a container, the theoretical number of surviving bacteria, as can be expected, is 99xc3x9710xe2x88x922 greater than  with a dose of 3.4 kGy and 99xc3x9710xe2x88x926 greater than  with a dose of 10.2 kGy.
At the present time, radiation sterilization of plastic medical devices such as syringes of polypropylene and artificial analyzer of polycarbonate has generally been carried out by applying 25 kGy, while in the present invention, the application of radiation for the purpose of sterilizing rubber stoppers for medicaments or rubber articles for medical treatments is generally carried out using a radiation dose of 5 kGy to 30 kGy in suitable manner.
Since the xcex3-rays is capable of exhibiting a higher transmission capacity (smaller attenuation coefficient), there is no large difference between the absorbed doses of an incident surface and back surface or adjacent reincident surfaces. That is, the method using xcex3-rays is a preferred means as a method of uniformly sterilizing a number of articles to be irradiated in the form of a singly wrapped state. Application of electron beam having a large dose results in marked reduction of an amount of a crosslinking agent in the prior art and thus, can be used as a method of crosslinking raw rubber (utilizing formation of polymer free radicals). Accordingly, this is a means capable of obtaining a finally aimed quality and property level of a rubber article for a medicament or medical treatment by subjecting a previously molded TPE (TPR) to secondary crosslinking (or post-crosslinking) or as in Examples 4 to 6 (Table 1), by subjecting a molding obtained by crosslinking a previously molded and pressed product (heating in a primary shaping stage) and adding a very small amount of crosslinking agent required for molding an original form to application of electron beam (secondary crosslinking).
The inventors have made various efforts and consequently, have found that when a rubber stopper for a medicament comprising butyl rubber excellent in sealing property is sterilized by application of radiation, with the proviso, as a primary optimum sterilizing condition, that electron beam is selected as a beam source and the degree of microorganism contamination on the surface of an article to be sterilized is low, use of a rubber stopper which is designed to decrease its density, in particular, to at most 0.95, so that electron beam is sufficiently transmitted by the application of a dose as low as possible for sterilizing and in a short period of time, is effective for readily transmitting radiation and advancing the radiation treatment with less oxidation and deterioration of the resin. The present invention is based on this finding.
In this case, the oxidation and deterioration of the resin is caused by such a phenomenon that polymer radicals are reacted with oxygen dissolved or diffused from the outside to form peroxy radicals (xe2x80x94O* *Oxe2x80x94) and the quarternary carbon part is cut to give Rxcx9cxe2x80x94Cxe2x95x90O and the molecular principal chains are cut to reduce the molecular weight (i.e. phenomenon occurring with passage of time) and that the principal chains are directly cut by radiations such as xcex3-rays, electron beam, etc. (i.e. phenomenon occurring directly after irradiation).
For the purpose of decreasing the density of the rubber composition of the present invention or its crosslinked product to at most 0.95, the blending proportion of components is controlled depending on the relationship of densities of IIR member, that is, IIR less than C-IIR and B-IIR less than XL-IIR or the blending proportion of additive components to be added such as thermoplastic resins, organic auxiliary agents, fillers, etc. is controlled, thus obtaining the relationship of dxe2x89xa60.95.